Mitochondrial dysfunction and protein aggregation (which is partly due to the decline of the ubiquitin proteasome system, UPS), are two commonly observed features of aging and age-related neurodegenerative diseases. There has been considerable recent interest in the ways in which the UPS interacts with mitochondria, particularly in the area of mitochondrial dynamics and quality control. It is not known if the age-related decline in proteasome efficiency could disrupt mitochondrial dynamics and quality control, causing mitochondrial dysfunction. In this study, I have used live-cell imaging to assess the effect of the UPS on mitochondrial dynamics in primary neurons. I found that complete disruption of the UPS greatly decreased mitochondrial motility, fission and fusion, whereas pharmacological inhibition of the deubiquitinase enzyme UCHL1 (which causes a physiologically relevant decline in the UPS) did not disrupt mitochondrial dynamics. Furthermore, I found that in UCHL1 knockout mice, mitochondria are not deficient in respiratory chain complexes I and IV; compromising the UPS does not cause mitochondrial dysfunction. UCHL1 knockout mice have a neurodegenerative phenotype characterized by impaired hind-limb function, tremor and kyphosis. Using immunohistochemistry, I demonstrated synaptic and axonal loss at the distal regions of long sensory axons that target the brainstem and cerebellum. The neuropathology of UCHL1 knockout mice is characterized by axonal spheroids, large axonal swellings containing synaptophysin, mitochondria and neurofilaments, which share some characteristics with spheroids that occur during ageing in human brains. I also studied the progression of axonal dystrophy in UCHL1 knockout mice and found that the accumulation of synaptophysin transport vesicles is central to axonal spheroid formation. Furthermore, I investigated whether the UPS is impaired in patients with mitochondrial disease, however found no evidence to suggest this. These findings indicate that the function of the UPS and mitochondria may be less tightly linked than previously thought.